The MOE Key Laboratory for Standardization of Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
J Appl Toxicol. 2020 Nov;40(11):1534-1544. doi: 10.1002/jat.4004. Epub 2020 Jul 3.
Herbal drug-induced liver injury has been reported worldwide and gained global attention. Thousands of hepatic sinusoidal obstruction syndrome (HSOS) cases have been reported after consumption of herbal medicines and preparations containing pyrrolizidine alkaloids (PAs), which are natural phytotoxins globally distributed. And herbal medicines, such as Gynura japonica, are the current leading cause of PA-induced HSOS. The present study aimed to reveal the mechanism underlying the hepatotoxicity of seneciphylline (Seph), a main PA in G. japonica. Results showed that Seph induced severe liver injury through apoptosis in mice (70 mg/kg Seph, orally) and primary mouse and human hepatocytes (5-50 μM Seph). Further research uncovered that Seph induced apoptosis by disrupting mitochondrial homeostasis, inducing mitochondrial depolarization, mitochondrial membrane potential (MMP) loss, and cytochrome c (Cyt c) release and activating c-Jun N-terminal kinase (JNK). The Seph-induced apoptosis in hepatocytes could be alleviated by Mdivi-1 (50 μM, a dynamin-related protein 1 inhibitor), as well as SP600125 (25 μM, a specific JNK inhibitor) and ZVAD-fmk (50 μM, a general caspase inhibitor). Moreover, the Seph-induced MMP loss in hepatocytes was also rescued by Mdivi-1. In conclusion, Seph induced liver toxicity via activating mitochondrial-mediated apoptosis in mice and primary hepatocytes. Our results provide further information on Seph detoxification and herbal medicines containing Seph such as G. japonica.
草药药物性肝损伤已在全球范围内报道，并引起了全球关注。在消费含有吡咯里西啶生物碱（PAs）的草药和制剂后，已经报告了数千例肝窦阻塞综合征（HSOS）病例，PAs 是全球分布的天然植物毒素。而一些草药，如 Gynura japonica，是目前导致吡咯里西啶生物碱引起的 HSOS 的主要原因。本研究旨在揭示 Seneciphylline（Seph），G. japonica 中的主要 PAs，引起肝毒性的机制。结果表明，Seph 通过诱导小鼠（70mg/kg Seph，口服）和原代小鼠和人肝细胞（5-50μM Seph）中的细胞凋亡引起严重的肝损伤。进一步的研究揭示，Seph 通过破坏线粒体稳态、诱导线粒体去极化、线粒体膜电位（MMP）丧失、细胞色素 c（Cyt c）释放和激活 c-Jun N-末端激酶（JNK）来诱导细胞凋亡。Mdivi-1（50μM，一种与动力蛋白相关蛋白 1抑制剂）、SP600125（25μM，一种特异性 JNK 抑制剂）和 ZVAD-fmk（50μM，一种通用 caspase 抑制剂）可以减轻 Seph 诱导的肝细胞凋亡。此外，Mdivi-1 还可以挽救 Seph 诱导的肝细胞中 MMP 的丧失。总之，Seph 通过激活小鼠和原代肝细胞中线粒体介导的凋亡引起肝毒性。我们的研究结果为 Seph 解毒和含有 Seph 的草药，如 G. japonica，提供了进一步的信息。
